Abnormal differentiation of superficial epithelia (e.g. the oral epithelium, epidermis) is an etiology shared among structural birth defects ranging from orofacial clefting to congenital ichthyosis. Linkage and association studies confirm that these genetic disorders have a genetic basis. However, in the case of orofacial clefting only about half of the heritable risk has been assigned to specific genes. Moreover, even in the case of ichthyosis, for which the causative genes of most of the common forms have been discovered, how the encoded proteins contribute to the differentiation of epidermis remains only poorly understood. Thus there remains a critical need to identify regulatory molecules that control the development of superficial epithelia, and to determine the interactions among them. Without a thorough understanding of the overall gene regulatory network responsible for the development of superficial epithelia, the efforts of genetic counselors wishing to predict risk for these disorders will continue to be severely limited. The zebrafish embryonic skin or periderm is a tractable model for superficial epithelia. Here we propose an in vivo, systems biology approach to deduce the architecture of the transcriptional network governing differentiation of zebrafish periderm. We will do so, in Aim 1, through extensive in vivo perturbation analyses, including epistasis experiments. Further, in Aim 2, with a combined approach using in vivo reporter studies and computational analyses we will identify cis-regulatory modules that control expression in the periderm. We will test the hypothesis that enhancers that are active at the same level within the network hierarchy will share a common organization. Our team includes an investigator with expertise in zebrafish embryology and one with expertise in genomic analysis of cis-regulatory modules in model systems. Successful completion of the proposed work will constitute the most exhaustive analysis of trans- and cis- acting elements driving differentiation of any vertebrate cell type conducted to date. Our expected outcome therefore is a dramatic advance in understanding the development of superficial epithelia, resulting in an improved ability to recognize sequence polymorphisms in coding and regulatory DNA and that are pathogenic for diseases of epithelial differentiation, which include disorders of skin and oro-facial clefting.

Public Health Relevance

Impaired differentiation of superficial epithelia, which include epidermis and oral epithelium, can cause structural birth defects, including rare but life-threatening defects in epidermal permeability barrier, and the common birth defect cleft lip and palate. Such diseases result from disruption of the gene regulatory network governing differentiation of superficial epithelia;however, this network is poorly understood. Here we propose an in vivo, systems biology approach to delineating this network in zebrafish, yielding a framework for developing the next generation of diagnostic tools and therapies for diseases of superficial epithelium differentiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE023575-01A1
Application #
8557276
Study Section
Special Emphasis Panel (ZRG1-CB-J (59))
Program Officer
Scholnick, Steven
Project Start
2013-07-19
Project End
2018-05-31
Budget Start
2013-07-19
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$377,500
Indirect Cost
$127,500
Name
University of Iowa
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Peyrard-Janvid, Myriam; Leslie, Elizabeth J; Kousa, Youssef A et al. (2014) Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development. Am J Hum Genet 94:23-32
Wang, Qinchuan; Lin, Jenny Li-Chun; Erives, Albert J et al. (2014) New insights into the roles of Xin repeat-containing proteins in cardiac development, function, and disease. Int Rev Cell Mol Biol 310:89-128